Université Grenoble-Alpes, Centre National de la Recherche Scientifique, Grenoble INP, TIMC CNRS UMR 5525, Grenoble, France.
Laboratory for Epigenetics and Environment, Centre National de Recherche en Genomique Humaine, CEA - Institut de Biologie François Jacob, University Paris Saclay, Evry, France.
Environ Health Perspect. 2023 Apr;131(4):47011. doi: 10.1289/EHP11559. Epub 2023 Apr 14.
High-dimensional mediation analysis is an extension of unidimensional mediation analysis that includes multiple mediators, and increasingly it is being used to evaluate the indirect omics-layer effects of environmental exposures on health outcomes. Analyses involving high-dimensional mediators raise several statistical issues. Although many methods have recently been developed, no consensus has been reached about the optimal combination of approaches to high-dimensional mediation analyses.
We developed and validated a method for high-dimensional mediation analysis (HDMAX2) and applied it to evaluate the causal role of placental DNA methylation in the pathway between exposure to maternal smoking (MS) during pregnancy and gestational age (GA) and birth weight of the baby at birth.
HDMAX2 combines latent factor regression models for epigenome-wide association studies with tests for mediation and considers CpGs and aggregated mediator regions (AMRs). HDMAX2 was carefully evaluated using simulated data and compared to state-of-the-art multidimensional epigenetic mediation methods. Then, HDMAX2 was applied to data from 470 women of the Etude des Déterminants pré et postnatals du développement de la santé de l'Enfant (EDEN) cohort.
HDMAX2 demonstrated increased power in comparison with state-of-the-art multidimensional mediation methods and identified several AMRs not identified in previous mediation analyses of exposure to MS on birth weight and GA. The results provided evidence for a polygenic architecture of the mediation pathway with a posterior estimate of the overall indirect effect of CpGs and AMRs equal to lower birth weight representing 32.1% of the total effect [standard deviation ]. HDMAX2 also identified AMRs having simultaneous effects both on GA and on birth weight. Among the top hits of both GA and birth weight analyses, regions located in , , and also mediated the relationship between GA and birth weight, suggesting reverse causality in the relationship between GA and the methylome.
HDMAX2 outperformed existing approaches and revealed an unsuspected complexity of the potential causal relationships between exposure to MS and birth weight at the epigenome-wide level. HDMAX2 is applicable to a wide range of tissues and omic layers. https://doi.org/10.1289/EHP11559.
高维中介分析是单维中介分析的扩展，包括多个中介，并且越来越多地用于评估环境暴露对健康结果的组学层间接影响。涉及高维中介的分析提出了几个统计问题。尽管最近已经开发了许多方法，但对于高维中介分析的最佳方法组合尚未达成共识。
我们开发并验证了一种高维中介分析方法（HDMAX2），并将其应用于评估胎盘 DNA 甲基化在母亲怀孕期间吸烟（MS）暴露与婴儿出生时胎龄（GA）和出生体重之间的途径中的因果作用。
HDMAX2 将全基因组关联研究的潜在因子回归模型与中介检验相结合，并考虑了 CpG 和聚合中介区域（AMR）。使用模拟数据仔细评估了 HDMAX2，并与最先进的多维表观遗传中介方法进行了比较。然后，将 HDMAX2 应用于 EDEN 队列的 470 名妇女的数据。
与最先进的多维中介方法相比，HDMAX2 显示出更高的功效，并确定了先前对 MS 暴露与出生体重和 GA 进行中介分析中未发现的几个 AMR。结果提供了中介途径多基因结构的证据，CpG 和 AMR 的总体间接效应的后验估计值等于较低的出生体重，占总效应的 32.1%[标准差]。HDMAX2 还确定了 AMR 对 GA 和出生体重同时具有影响。在 GA 和出生体重分析的前几个命中中，位于 、 和 的区域也介导了 GA 和出生体重之间的关系，表明 GA 和甲基组之间的关系存在反向因果关系。
HDMAX2 优于现有方法，并揭示了在全基因组范围内，MS 暴露与出生体重之间潜在因果关系的意想不到的复杂性。HDMAX2 适用于广泛的组织和组学层。https://doi.org/10.1289/EHP11559.
